Sulfated pentagalloylglucoside is a potent, allosteric, and selective inhibitor of factor XIa.

Abstract

Inhibition of factor XIa (FXIa) is a novel paradigm for developing anticoagulants without major bleeding consequences. We present the discovery of sulfated pentagalloylglucoside (6) as a highly selective inhibitor of human FXIa. Biochemical screening of a focused library led to the identification of 6, a sulfated aromatic mimetic of heparin. Inhibitor 6 displayed a potency of 551 nM against FXIa, which was at least 200-fold more selective than other relevant enzymes. It also prevented activation of factor IX and prolonged human plasma and whole blood clotting. Inhibitor 6 reduced V(MAX) of FXIa hydrolysis of chromogenic substrate without affecting the K(M), suggesting an allosteric mechanism. Competitive studies showed that 6 bound in the heparin-binding site of FXIa. No allosteric small molecule has been discovered to date that exhibits equivalent potency against FXIa. Inhibitor 6 is expected to open up a major route to allosteric FXIa anticoagulants with clinical relevance.

• Authors: Rami A Al-Horani, Pooja Ponnusamy, Akul Y Mehta, David Gailani, Umesh R Desai
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 3 Pg. 867-78 (Feb 14 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23316863 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glucosides
• Serine Proteinase Inhibitors
• Sulfuric Acid Esters
• sulfated pentagalloylglucoside
• Factor XIa

Topics

• Allosteric Regulation
• Carbohydrate Sequence
• Chromatography, Liquid
• Enzyme Activation
• Factor XIa (antagonists & inhibitors)
• Glucosides (chemistry, pharmacology)
• Hydrolysis
• Kinetics
• Magnetic Resonance Spectroscopy
• Molecular Mimicry
• Molecular Sequence Data
• Serine Proteinase Inhibitors (chemistry, pharmacology)
• Spectrometry, Mass, Electrospray Ionization
• Sulfuric Acid Esters (chemistry, pharmacology)
• Thrombelastography